Coronary disease is the leading cause of death in the United States. One of the major factors leading to this condition is the hardening and narrowing of arteries by atherosclerotic plaques. These plaques originate principally from macrophage-derived foam cells, which store elevated concentrations of esterifled cholesterol. Acyl-CoA cholesterol acyltransferase (ACAT) catalyzes the intracellular esterification of cholesterol with long chain coenzyme A-activated fatty acids. Therefore, ACAT may play an important role in the absorption of dietary cholesterol. An efficient ACAT inhibitor has the potential to function therapeutically as an anti-atherosclerotic agent by decreasing cholesterol absorption and limiting the conversion of macrophages into cholesterol ester-saturated foam cells. The purpose of this project is to develop an effective inhibitor for ACAT based upon the fundamental structure of helminthosporol, a phytotoxin that has shown moderate inhibitory activity. Unmasking the structural features most important to inhibitory activity will be central to the development of a therapeutic agent. Therefore, helminthosporol, two biogenetically-related metabolites known as prehelminthosporol and sorokinianin, and several minimized analogs will be prepared by total chemical synthesis. Synthetic access to all these targets will originate from a general route that can be diverted in the middle to late stages to prepare each analog. This common synthesis is based fundamentally upon a sequence of i) silyl-directed Nazarov cyclization, ii) vinylogous Darzen's condensation, and iii) divinylcyclopropane rearrangement to prepare the [3.2.1]-bicyclooctane nucleus that composes the helminthosporol natural products. Once the natural product and analogs have been prepared, a well-precedented in vitro assay that employs 14C-labeled-oleate will be used to determine the extent of ACAT inhibition in macrophages.